Biodegradable polymers are well known for their use in biomedical applications such as sutures, surgical clips, staples, implants, and drug delivery systems. These polymers include the polyglycolides, polylactides, polycaprolactones, polyanhydrides, polyorthoesters, polydioxanones, polyacetals, polyesteramides, polyamides, polyurethanes, polycarbonates, poly(amino acids), polyphosphazenes, polyketals, polyhydroxybutyrates, polyhydroxyalerates, and polyalkylene oxalates. Examples of their uses are described in U.S. Pat. No. 3,297,033 to Schmitt, U.S. Pat. No. 3,636,956 to Schneider, U.S. Pat. No. 4,523,591 to Kaplan, U.S. Pat. No. 3,773,919 to Boswell, U.S. Pat. No. 3,887,699 to Yolles, U.S. Pat. No. 4,155,992 to Schmitt, U.S. Pat. No. 4,379,138 to Pitt et al., U.S. Pat. No. 4,186,189 to Shalaby et al., U.S. Pat. No. 4,767,628 to Hutchinson, U.S. Pat. No. 4,530,840 to Tice, et al., and U.S. Pat. No. 4,891,225 and U.S. Pat. No. 4,906,474 to Langer.
All of the biodegradable polymers described in the foregoing patents are solid materials used to form solid articles such as sutures, staples, surgical clips, implants or microcapsules and microparticles. Because these polymers are solids, all of their applications in the biomedical field require that the polymeric structures be formed outside the body, and then inserted into the body for their use. Sutures, clips, and staples are normally placed in the body during a surgical procedure. Solid implants for drug delivery are either surgically placed or inserted into the body using large diameter trochars. Only the microparticles including microcapsules and microspheres can be injected using standard syringes and needles. However, the manufacture of microparticles and nanoparticles is a difficult process with many variables that have to be controlled to obtain reproducible drug delivery systems. These include solvent selection, polymer and drug concentration, temperature, stirring speed, drug loading, particle size, coating uniformity, and porosity. Because the drug is in contact with the polymer during the manufacturing steps and on storage, sterility and stability issues are normally encountered. In addition, a great deal of the drug is lost if the encapsulation efficiency is not high during the manufacturing process.
Dunn et al., in U.S. Pat. Nos. 4,938,763 and 5,278,201 have overcome the administration problems with the solid implants by dissolving the solid biodegradable polymers in a biocompatible solvent and injecting the solution into the body using standard syringes and needles where the polymer in the solution precipitates or coagulates upon contact with aqueous body fluid to form a solid implant matrix. The delivery system described in these patents offer a number of advantages including the ease of manufacture of the polymer solution, the incorporation of the drug into the polymer solution just prior to administration leading to increased drug and polymer stability as well as no loss of drug during the manufacturing process, and the ability to terminally sterilize the polymer solution as well as the drug. However, there are some disadvantages with this in-situ forming polymer system. Because the polymers used are solids with relative high molecular weights, the polymer solutions formed from the combination of the solid polymers and the biocompatible solvents are quite viscous. With the high solution viscosities, 18-21 gauge needles are required for administration and considerable injection force is needed. In addition, the viscous solutions are not easily injected into muscle tissue and the solid implants formed from these polymer solutions tend to cause local irritation of the muscular tissue. For this reason, the foregoing polymer solutions are normally injected subcutaneously where the material forms quite distinct and noticeable bumps.
Bezwada et al. in U.S. Pat. No. 5,442,033 have attempted to overcome the use of solvents in the Dunn delivery system and the formation of solid implant bumps by using liquid biodegradable polymers of caprolactone and lactide. In later patents including U.S. Pat. No. 5,631,015; U.S. Pat. No. 5,653,992; U.S. Pat. No. 5,599,852; U.S. Pat. No. 5,728,752; and U.S. Pat. No. 6,335,383, both Bezwada and Scopelianos et al. have extended this concept by using a variety of caprolactone, trimethylene carbonate, and ether lactone copolymers or terpolymers with glycolide, lactide, or p-dioxanone to form liquid biodegradable polymers which are injected into the body without the use of solvents to form liquid implants used as medical devices. Both Bezwada and Scopelianos indicate that the use of solvents with the Dunn delivery system is a major disadvantage which they have overcome with their liquid polymers. However, these liquid polymers are very viscous materials with viscosities normally much greater than 5,000 cP at 37° C., and they require large 16-18 gauge needles with special syringes and a high injection force for administration into the body. The high viscosities of the liquid polymers and the need for special syringes and large needles are major disadvantages of the Bezwada and Scopelianos systems.
Tipton et al. in U.S. Pat. No. 5,747,058 and Gibson et al. in U.S. Pat. No. 7,053,209 have found that highly viscous, nonpolymeric, non-water soluble liquid materials with viscosities of at least 5,000 cP at 37° C., can also be used as liquid implants for drug delivery. They further describe the use of biocompatible solvents to reduce the viscosity of the high viscosity nonpolymeric liquids to levels less than 1,000 cP so as to enable administration of the material into the body with smaller gauge needles. All of these materials are nonpolymeric and would be expected to show low viscosities when dissolved in a biocompatible solvent. Even solid nonpolymeric materials as described by Dunn et al. in U.S. Pat. No. 5,736,152, when dissolved in biocompatible solvents, form non-viscous solutions which can be injected into the body with standard syringes and needles to form nonpolymeric implants having a solid matrix that has a firm consistency ranging from gelatinous to impressionable and moldable, to a hard, dense solid. However, the problem with nonpolymeric materials is that their degradation times in the body cannot be varied, as they are nonpolymeric with only one molecular weight. In addition, their release characteristics cannot be modified by changing the molecular composition as can be achieved with polymeric materials.
Therefore, there exists a need for a method and composition for providing liquid polymeric implants with low viscosities for easy administration into the body using standard syringes and needles.
There also exists a further need for a method and composition for providing more syringeable liquid implants which are biodegradable and can be used as medical or surgical devices and/or controlled delivery systems.
In addition, there is the need for such liquid implants in which the polymer biodegradation and drug release characteristics can be varied over a wide range of time and rates.